1. Field of the Invention
This invention relates to pyrimido[1,2-a]quinoline-2-carboxylic acids and derivatives thereof and to their use as antiulcer agents. More particularly, it relates to 1-oxo-1H-6-substitutedpyrimido[1,2-a]quinoline-2-carboxylic acids, salts and esters thereof wherein the substituent is methoxy, ethoxy or piperidino which are useful as antiulcer agents.
2. Description of the Prior Art
Chronic gastric and duodenal ulcers, collectively known as peptic ulcers, are a common affliction for which a variety of treatments have been developed. The treatment depends upon the severity of the ulcer and may range from dietary and medical (drug) treatment to surgery. A wide variety of drugs have been used to treat ulcers; the most recent of which to gain widespread attention is carbenoxolone sodium, the disodium salt of the hemisuccinate of glycyrrhetinic acid. It is reported to prevent formation of and to accelerate healing of gastric ulcers in animals, including humans ("Carbenoxolone Sodium: A Symposium," J. M. Robson and F. M. Sullivan, Eds., Butterworths, London, 1968). However, its use is accompanied by undesirable aldosterone-like side effects, such as marked antidiuretic and sodium-retaining activity and, oftentimes, potassium loss, such that continued therapy with this agent often leads to hypertension, muscle weakness and, ultimately, congestive heart failure.
An effective treatment of peptic ulcers is, therefore, desirable. One which will effectively act upon gastric ulcers, without causing the aldosterone-like side effects observed with carbenoxolone, is especially desirable.
The synthesis of a 1H-pyrimido[1,2-a]quinoline appears to have first been reported by Antaki et al., J. Chem. Soc., pages 551-555 (1951), who condensed 2-chloroquinoline with ethyl .beta.-amino crotonate in the presence of anhydrous potassium carbonate and a trace of copper bronze to produce 1-oxo-1H-3-methylpyrimido[1,2-a]quinoline. No utility for the compound was reported.
Antaki, J. Am. Chem. Soc., 80, 3066-9 (1958), reports the condensation of 2-aminoquinoline and ethylethoxymethylenecyanoacetate to give ethyl 2-quinolylaminomethylenecyanoacetate which when distilled under reduced pressure afforded 1-oxo-1H-pyrimido[1,2-a]quinoline-2-carbonitrile. The compound demonstrated antischistosomal action.
Richardson et al., J. Med. Chem., 15, 1203-6 (1972) describe ethyl 1-oxo-1H-pyrimido[1,2-a]quinoline-2-carboxylate and report it to be inactive as an antimicrobial agent. When tested for antiulcer activity by the method described herein, it was found to be inactive via the oral route of administration.
Gupta et al., Indian J. Chem., 9, 201-206 (1971) report the preparation of ethyl 1-oxo-1H-6-hydroxypyrimido[1,2-a]quinoline-2-carboxylate and its investigation as a hypoglycemic agent. However, the compound described therein is believed to be incorrectly identified since it differs in chemical properties from the named compound prepared by the method described in this application. Ethyl 1-oxo-1H-6-hydroxypyrimido[1,2-a]quinoline-2-carboxylate when tested for antiulcer activity by the method described herein exhibited no activity by the oral route of administration.